Variable phenotypic presentation of a novel FOXF1 missense mutation in a single family.
Variable phenotypic presentation of a novel FOXF1 missense mutation in a single family.
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单一家族中新型 FOXF1 错义突变的可变表型表现。
DOI：
10.1002/ppul.23425
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发表时间：
2016
影响因子：
3.1
通讯作者：
Kerem,Eitan
中科院分区：
文献类型：
--
作者：
Reiter,Joel;Szafranski,Przemyslaw;Breuer,Oded;Perles,Zeev;Dagan,Tamir;Stankiewicz,Paweł;Kerem,Eitan
foxf1转录因子基因的杂合突变与肺泡毛细血管发育不良伴肺静脉错位（ACDMPV）有关，ACDMPV是一种肺部发育障碍，典型表现为肺动脉高压和早期死亡。有证据表明单倍不全和部分父系印记。我们提出了一个家庭，有几个受影响的成员，具有非常可变的表型。患者指标患者出生数小时后出现严重肺动脉高压。她现在3岁，正在接受最大限度的肺动脉高压治疗、慢性类固醇和氧气治疗。患者的一个兄弟姐妹死于16天肺动脉高压和环状胰腺，符合经典ACDMPV。方法对索引病例进行全外显子组测序。Sanger测序证实了鉴定出的变异，并在其余家庭成员中进行了测试。通过PCR扩增、克隆、测序和相邻单核苷酸多态性鉴定来确定亲本来源。对无症状携带者进行超声心动图检查。结果全外显子组分析显示foxf1基因中存在一种新的、可预测的杂合错义突变，g.c r16:86544406 C> a NM_001451, c.C231A, p.F77L。突变发生在父亲身上，从头开始，在合子后早期，血液中70%的体细胞嵌合体出现在祖父染色体上。在先证者的无症状姐妹中也存在，发现肺静脉回流部分异常。结论foxf1突变可能具有非常不同的表型，可能是由于体细胞嵌合和复杂的基因调控，包括基因位点的非正统印记。先证者的长期生存表明需要积极的治疗。儿科肺科杂志2016；51:921 - 927。©2016 Wiley期刊公司
BackgroundHeterozygous mutations in theFOXF1transcription factor gene are implicated in alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a developmental disorder of the lungs classically presenting with pulmonary hypertension and early demise. Evidence has suggested haploinsufficiency and partial paternal imprinting. We present a family with several affected members with an extremely variable phenotype.PatientsThe index patient presented several hours after birth with severe pulmonary hypertension. She is now 3‐years old, thriving on maximal pulmonary hypertension therapy, chronic steroids, and oxygen. One of the patient's siblings died at 16 days with pulmonary hypertension and an annular pancreas, consistent with classical ACDMPV.MethodsWhole exome sequencing was performed in the index case. The identified variant was confirmed by Sanger sequencing, and tested in the remaining family members. Parental origin was determined by PCR amplification and cloning, sequencing, and identification of adjacent single nucleotide polymorphisms. Echocardiography was performed in the asymptomatic carriers.ResultsWhole exome analysis revealed a novel, predictably pathogenic heterozygous missense mutation, g.chr16:86544406 C>A NM_001451, c.C231A, p.F77L, in theFOXF1gene. The mutation arose in the father, de novo, early postzygotically, with 70% somatic mosaicism in the blood, on the grandpaternal chromosome. It was also present in the proband's asymptomatic sister, found to have partial anomalous pulmonary venous return.ConclusionFOXF1mutations may have an extremely variable phenotype, possibly as a result of somatic mosaicism and complex gene regulation including unorthodox imprinting of the gene locus. The prolonged survival of the proband suggests the need for aggressive treatment.Pediatr Pulmonol. 2016; 51:921–927. © 2016 Wiley Periodicals, Inc.
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